Genome-wide association studies (GWASs) and follow-up studies of the most promising GWAS hits by the NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC) and other members of the International IBDGC (IIBDGC) have been highly successful, as judged by the number of regions (>150) with genome-wide significant association signals in Crohn's disease (CD), ulcerative colitis (UC), or both forms of IBD; and their illumination of the probable involvement of specific biological pathways such as the IL-23/T helper 17 (Th17) immune pathway, autophagy, and mucosal barrier function in IBD pathogenesis. However, few of the genetic variants with the strongest association signals are predicted to change amino acid sequence or have other effects on protein structure. Most are in intronic or intergenic regions where they do not have immediately obvious functional effects. Together, they explain a modest proportion of the estimated heritability of CD and UC. Since effect sizes of individual risk-associated alleles are generally small, disease susceptibility probably arises from an accumulation of multiple small effects on biological pathways. Additional genetic studies that aim to fill in gaps in our understanding of the heritability should be complemented with the application of new statistical and computational methods to identify the strongest candidate IBD-causal variants in a gene network context. Coordinated investigation of the effects of candidate risk alleles on specific biological pathways in relevant tissues and cell types by NIDDK IBDGC Genetic Research Centers (GRCs) and other groups conducting ancillary studies is an essential strategy to dissect disease pathogenesis. IBD GWAS hits in multiple IL-23/Th17 immune pathway genes; GWAS hits that also implicate IL-23 signaling in ankylosing spondylitis, Behcet's disease, leprosy, and psoriasis; and a strong IL-23/Th17 immune pathway research environment at the University of Pittsburgh prompted us to begin exploration of the role of IBD-associated genetic variants in Th17 biology. Our Specific Aims are: Aim 1. Maintain an infrastructure for recruitment of study subjects, phenotyping, and biosample collection for NIDDK IBDGC Steering Committee-approved consortium-wide, GRC-specific, and ancillary studies; Aim 2. Participate in the design and execution of NIDDK IBDGC and IIBDGC genetic studies that aim to identify the strongest candidate IBD-causal variants; Aim 3. Examine the relationship between IBD-associated genetic variants and differential gene expression traits induced in activated effector memory T cells by inflammatory mediators (IL-23, IL-1, and PGE2) known to be overexpressed in inflamed IBD tissues, to modulate Th17 function, and to be related to IBD-associated genes. PUBLIC HEALTH RELEVANCE: Inflammatory bowel disease (IBD) has both genetic and non-genetic risk factors. Genetic variation that has been associated with this complex disorder so far explains only a modest proportion of the estimated disease heritability, so additional genetic studies are needed to more fully explain the heritability. To learn how IBD arises and progresses, we must also understand how the genetic variation associated with IBD affects human biology. We propose to continue supporting the NIDDK IBD Genetics Consortium in all its activities and to explore the effect of genetic variants associated with IBD on immune biology.